Nicotine (NIC) addiction remains a significant public health concern and financial burden in America. Despite the recent development of FDA-approved medications, rates of smoking and number of successful quit attempts remain unchanged thus warranting an enhanced understanding of pharmacological factors involved in NIC abuse for improved medication development. Effective treatments for NIC abuse rely on a firm understanding of the mechanisms mediating the behavioral effects of NIC. Behavioral and neurochemical evidence supports the hypothesis that the reinforcing and subjective effects of NIC are primarily attributed to a42 nACh receptor-stimulated dopamine (DA) release. Therefore, this application will utilize a nonhuman primate model to elucidate the role of nACh (a42, a62, a7, a34) and DA receptors (D2-like receptors including the D3 receptor subtype) in mediating the discriminative stimulus (SD) effects of NIC, effectively modeling the subjective effects in humans that contribute to the development of NIC dependence. I will also test the hypothesis that chronic NIC exposure (as seen in smokers) alters the behavioral and neurochemical effects of NIC, including measures of nACh and D2-like receptor function. First, adult cynomolgus monkeys will be trained to discriminate NIC from saline using a cumulative dosing procedure. Partial agonists and antagonists selective for subtypes of the DA and nACh receptor systems will be tested for their ability to substitute and/or attenuate the SD effects of NIC. Second, the progressive effects of chronic NIC exposure on physiological, behavioral, and neurobiological baselines will be assessed using telemetry, NIC discrimination, positron emission tomography (PET), and unconditioned behaviors. Monkeys will receive twice-daily non- contingent NIC injections of the training dose of NIC over a 20-day period. This model will allow for systematic investigation of variables involved in chronic NIC exposure to better understand the behavioral etiology and underlying neurobiological state of NIC use, analogous to the progression from recreational use to NIC dependence experienced by smokers. Changes in DA D2-like and a42 nACh receptor availability will be examined using PET imaging. Additionally, the effects of nACh and DA receptor subtype selective compounds will be re-examined on NIC discrimination to examine the neuropharmacological response to these compounds following chronic NIC exposure. These studies will enhance the understanding of the progressive behavioral and neurobiological effects associated with NIC abuse to ultimately provide translational insights into novel pharmacotherapeutic targets and treatment strategies for NIC addiction.